Woestenberg, Petra J. BSc*; van Lier, Alies MSc*; van der Maas, Nicoline A.T. MD*; Drijfhout, Ingrid H. MD†; Oomen, Petra J.‡; de Melker, Hester E. PhD*
Timely vaccination is important to protect infants from vaccine-preventable infections; postponing vaccination leads to a longer period of increased susceptibility and therefore to an increased risk of infection. Timely vaccination is even more important for preterm (PT) and low birth weight (LBW) infants because they are at increased risk of infectious diseases due to the lower amount of maternal antibodies that are mainly transferred in the last trimester of pregnancy1–4 and the immaturity of their immune system.5,6 PT and LBW infants have for example a higher risk of (hospitalization due to) pertussis, compared with full term (FT) or normal birth weight (NBW) infants.7
To protect PT and LBW infants against infectious diseases, the Dutch National Institute for Public Health and the Environment (RIVM) recommends vaccination of PT and LBW infants according to the standard guidelines of the Dutch National Immunization Programme (NIP). It is advised not to correct for gestational age (GA) or birth weight (BW) in the timing of vaccination.8 Following these standard guidelines, it is recommended that the first diphtheria, tetanus, acellular pertussis and inactivated polio vaccine (DTaP-IPV) be given at 2 months chronological age, that is, between 6 and 9 weeks of age.8 In various other countries (United Kingdom, France, Germany, United States), it is recommended that the first DTaP and IPV vaccination be given at 2 months chronological age as well, with no correction for GA or BW.9–12 The timeliness of the first dose is especially important because of the risk of pertussis. One dose already gives (partial) protection13,14 and a delayed administration of the first dose usually means delayed administration of subsequent doses as well due to the standard time interval of 4 weeks between the first 3 doses.8
Although PT and LBW infants may have a lower immune response following vaccination than FT and NBW infants, multiple studies have demonstrated an overall sufficient immune response of both PT and LBW infants after immunization at 2 months of age.5,6,12,15
PT and LBW infants can temporally experience recurrences or an increase of specific adverse events such as apnea and bradycardia after the first DTaP-IPV immunization, especially if the infant is still hospitalized at 2 months chronological age.16–18 However, in a recent study, it was concluded that the vaccination of PT infants at 2 months of age is safe in terms of adverse events.19 In general, it is accepted that the benefits of early vaccination outweigh any potential safety risks and therefore the potential adverse events should not be a reason to postpone vaccination. Despite the recommendation to vaccinate PT and LBW infants according to the standard guidelines and data confirming adequate immune response and safety, several studies have shown a delay in the immunization of LBW infants compared with NBW infants.20–24
In the Netherlands there are also indications of postponement of immunization in PT/LBW infants, but no reliable figures were available. Therefore, we studied the relationship between GA/BW and the timing of the first DTaP-IPV vaccination in the Netherlands during the first year of life and characteristics associated with the timeliness of vaccination.
MATERIALS AND METHODS
Setting and Study Population
In the Netherlands, a 2-3-4-11 months’ immunization schedule is used for the DTaP-IPV vaccination in the first year of life. In daily practice, the combination vaccine DTaP-IPV and Haemophilus influenzae type b vaccine was administered in the study period (2006–2010) simultaneously with the 7-valent conjugated pneumococcal vaccine. Parents are invited by letter, including personalized vaccination cards for each vaccination event, to get their children vaccinated according to the NIP. If parents do not respond, a reminder is sent. Vaccinations are administered at regional level by a network of child health care centers and municipal health services during routine visits. Attendance to these visits is high, up to 99%. In addition to vaccinations, these visits also include physical checkups with full medical history, screening of growth and development and vision and hearing testing.25 Vaccination is voluntary and free of charge.26
The study population included all children born in the Netherlands between January 1, 2006 and December 31, 2010 who were registered in the population registry with a known residence. We excluded children who died or left the Netherlands within 1 year after birth because these children had less chance to be vaccinated on time due to reasons that cannot be influenced by the NIP (disease, movement). Therefore, we only included children who all had the same chance to be vaccinated within the same period of 1 year. Furthermore, children with an unknown GA and/or BW were excluded because we could not categorize them. We also excluded the cases with a GA of <175 or >304 days because of the absence of reference BW norms for these values.27 Moreover, we observed unrealistic values in terms of BW relative to the GA. To exclude these unrealistic values, we adopted a method used by Visser et al28 who removed all observations outside the mean BW ± 3 times the standard deviation. However, in our study, this method resulted in the exclusion of a considerable number of cases that we considered realistic. Therefore, we adjusted the method and excluded the cases with a BW outside the mean BW ± 4 times the standard deviation for the corresponding GA in weeks, for boys and girls separately. This procedure led to 1004 (0.1%) outliers. Finally, we excluded unvaccinated children because we wanted to study factors associated with the timeliness of the first vaccination and not factors associated with no vaccination (such as the known religious reasons to reject vaccination). There were no differences in the vaccination coverage by GA or BW: in all groups, 98–99% of the children were vaccinated at least once with DTaP-IPV.
We used data from Præventis, a national computerized immunization register in which all administered vaccinations of the NIP are registered based on vaccination cards. Præventis also contains data from the national population registry and the newborn screening.29 During this newborn screening that takes place within 7 days after birth, the duration of pregnancy and BW of the infant are reported by the parents and registered in Præventis.30
We extracted individual data from Præventis (anonymously) on background characteristics (date of birth, gender, current residence, country of birth of the parents), information about the first DTaP-IPV vaccination [date of administration, executive organization: child health care centre, general practitioner, midwife or hospital with or without a neonatal intensive care unit (NICU)] and newborn screening (GA, BW). To ensure the privacy of the children, the lowest level for current residence was the municipality. Based on the municipality, the infants were categorized into 1 of the 28 municipal health service regions of the Netherlands.31
Because socioeconomic status (SES) and the urbanization rate were not available at individual level, we used data from the Netherlands Institute for Social Research and Statistics Netherlands as a proxy for the individual value.32,33 SES is an indicator based on the average income per household in a given postcode area as well as the percentage of households with low income, without a paying job and with a low level of education.34 Data on the SES and urbanization rate were available at the postcode level. Because the lowest level of current residence in our study was municipality, we first had to aggregate the data to the municipality level by calculating the weighted mean of the different postcode areas per municipality.
The infants were classified into different groups based on their GA and BW.
Gestational age (GA):
- -Extreme preterm (EPT), GA: <32 weeks,
- -Preterm (PT), GA: 32–36 weeks,
- -Full term (FT), GA: ≥37 weeks.
Birth weight (BW):
- -Extremely low birth weight (ELBW), BW: <1000 g,
- -Very low birth weight (VLBW), BW: 1000–1499 g,
- -Low birth weight (LBW), BW: 1500–2499 g,
- -Normal birth weight (NBW), BW: ≥2500 g.
Furthermore, an infant was considered being small for gestational age (SGA) when the BW was in the lowest 10% values according to Dutch reference norms (taking into account their GA and sex).27 In the Netherlands, it is recommended that infants be vaccinated between 6 and 9 weeks of age.8 Vaccination within 9 weeks of age (<70 days) was therefore considered on time.
The individual age at the first DTaP-IPV vaccination was calculated, as well as the median age and 5th and 95th percentiles for all groups of GA and BW. In addition, the proportion of infants vaccinated on time was calculated.
To study characteristics possibly associated with the timeliness of vaccination, we calculated the percentage of EPT, PT and FT infants vaccinated on time by the following variables: gender, birth cohort, SES (municipality level), urbanization rate (municipality level), SGA, executive organization of the vaccination (hospital with or without a NICU or other), country of birth of parents and municipal health service region. We used the Fisher’s exact test to check for statistically significant differences in the percentage of infants vaccinated on time compared with the reference category. The analyses were performed for all infants and EPT, PT and FT infants separately because of the expected differences between these groups due to the differences in setting; EPT and PT infants are more often still hospitalized when they reach the eligible age for vaccination while FT infants are normally at home. To correct for multiple testing, the Benjamini-Hochberg method was applied with a false discovery rate of 0.05 (4 groups × 53 tests each = 212 tests in total).35
Moreover, we performed multivariable Cox regression analyses on the outcome: age at the first DTaP-IPV vaccination in days. A higher hazard therefore means a timelier vaccination, which is desirable. These analyses were also performed for EPT, PT and FT infants separately and all variables mentioned above were included. P < 0.05 was considered statistically significant. The analyses were performed using SPSS 19.0.
The final study population included 883,747 infants (Fig. 1). The relative size of the groups by GA and BW are presented in Table 1.
Timeliness of the First DTaP-IPV Vaccination
The median age at the first DTaP-IPV vaccination was the highest for EPT (and ELBW) infants and the lowest for FT (and NBW) infants. The proportion of infants receiving the first vaccination on time was higher for the group of infants with a higher GA/BW (Table 1 and Figs. 2 and 3).
Characteristics Associated With the Timeliness of the First DTaP-IPV Vaccination
The percentages of infants receiving the first vaccination on time according to different characteristics are presented in Table 2. The timeliness of vaccination increased over time, varying from 77.0% vaccinated on time in 2006 to 84.7% in 2010. This positive trend was seen for all groups of GA.
The differences in the proportion of infants vaccinated on time by SES were the most obvious in EPT infants; 63.2% of the EPT infants with a low average SES at the municipality level were vaccinated on time compared with 73.0% of the EPT infants with a high SES. Infants living in a very highly urbanized municipality were less often vaccinated on time than infants living in a place less urban. This was observed for all categories of GA. The percentage of infants with a timely first dose was higher among infants who were not SGA than among infants who were SGA. Again, this was observed for all categories of GA. Vaccinations performed in a hospital instead of another organization were more often on time in EPT infants, but less often on time in PT infants. In FT infants, only vaccinations performed in a hospital with a NICU were less often on time. Overall, vaccinations performed in hospitals without a NICU were more often on time compared with hospitals with a NICU. The proportion of infants that received the first vaccination on time was lower for infants of whom the country of birth of the parents was unknown. Having parents who were both born in the Netherlands was associated with the highest proportion of infants vaccinated on time among PT and FT infants. Among EPT infants, the infants with parents who were both born in the Netherlands Antilles received the first dose on time most often. Finally, there were large regional differences in the timeliness of the first vaccination; the proportion vaccinated on time by municipal health service region ranged from 51.5% to 84.3% for EPT, 65.6–85.6% for PT and 72.6–91.0% for FT infants (Appendix Table A1).
Results from the Cox regression analyses are presented in Table 3. The following characteristics were associated with a less timely first vaccination in EPT, PT and FT infants after adjustment for the other variables: born in a less recent birth cohort and living in a very highly urbanized municipality. Municipal health service region was also associated with the timing of the first vaccination in all groups of infants (Appendix Table A2) as was the country of birth of the parents. Having parents who were both born in the Netherlands Antilles (in EPT infants) and having 1 parent born in the Netherlands and the other parent born in Turkey (in FT infants) were associated with a more timely first vaccination compared with having parents who were both born in the Netherlands. Only in FT infants, SES was associated with the timeliness of vaccination, but no clear trend was seen. SGA was associated with a less timely first dose in EPT and PT infants, but not in FT infants. In EPT infants, vaccinations performed in a hospital were timelier than those performed by another organization. In contrast, being vaccinated in a hospital was associated with a less timely vaccination in PT and FT infants. However, in FT infants, this was only true for hospitals with a NICU.
To our knowledge, this is the first time the timeliness of the first DTaP-IPV vaccination in preterm and low birth weight infants has been assessed in the Netherlands. In our study, the timeliness of the first DTaP-IPV vaccination was higher for the group of infants with a higher GA/BW. Not only 34% of the EPT and 24% of the PT infants but also 18% of the FT infants were vaccinated later than recommended (≥70 days). Vaccination was performed later than recommended in 44% of the ELBW, 33% of the VLBW, 25% of the LBW and 18% of the NBW infants.
As a consequence of these delays, infants are at increased risk of vaccine-preventable infections, such as pertussis, which is endemic in the Netherlands.36 The increased risk is even more evident in preterm infants because they are more vulnerable to infections.5,7 Studies have shown that even a single DTaP immunization has an effect on preventing (hospitalization due to) pertussis and that postponing vaccination indeed leads to more cases.13,14 Based on the reported number of nonvaccinated pertussis cases in the Netherlands from 2006 to 2010 (source: notification data), it is estimated that a timely first vaccination could have prevented 13–22% of the pertussis cases below the age of 1 year (assuming that the parents were willing to vaccinate). In this period, 99 cases (<1 year) contracted pertussis after the 69th day of life without being vaccinated and another 74 cases (<1 year) contracted pertussis between the 42nd and 70th day of life without being vaccinated (data not shown). The latter group could potentially have been vaccinated at the age of 6–9 weeks. A delayed administration of the first dose usually means delayed administration of subsequent doses as well due to the standard time interval of 4 weeks between doses and the fact that the first 3 DTaP-IPV doses are advised at, respectively, 2, 3 and 4 months of age.8 Therefore, it is extremely important to start the first vaccination on time.
Although a notable percentage of infants is vaccinated later than recommended, it seems that infants in the Netherlands receive their first vaccination on time more often compared with other countries. Children in our population are younger at their first vaccination compared with the results of Langkamp et al22 and Tillmann et al.24 Batra et al23 assessed the vaccination coverage by BW at 90 days of age instead of <70 days. The vaccination coverage at 90 days in our data (Fig. 3) is also higher than that reported by Batra et al,23 especially among ELBW infants.
The finding that Dutch infants receive their first vaccination more often on time compared with other countries is perhaps the result of ongoing efforts in the Netherlands to improve the timeliness of vaccination in general.37 These ongoing efforts are likely also the reason for the improvements in the timeliness of the first vaccination within the Netherlands during the period 2006–2010. Since 2007, reports on the timeliness of the first DTaP-IPV vaccination are produced regularly in the Netherlands. The managers of the child health care centers are informed on this topic annually and possible interventions for improvement are discussed with the executive child health care workers at the regional level. Examples of solutions for improvement are administering the first vaccination during an earlier consult if the child is already old enough, make an appointment for 2 (instead of 1) consults ahead and discussion of the relevance of the timeliness of the first DTaP-IPV vaccination with colleagues responsible for the planning of the consults. With regard to preterm infants in particular, there is special emphasis on the importance of the timeliness of vaccination among these children during internal trainings and in the implementation rules of the Dutch NIP.
Our results suggest that both GA and BW have an effect on the timeliness of the first vaccination because EPT and PT infants who were also SGA were vaccinated later in time than EPT and PT infants with a normal BW for the corresponding GA. Our results also indicate that reduced health is a risk factor for a delayed first vaccination. PT and FT infants received the first vaccination in a less timely manner when vaccination took place in a hospital. The medical reason for the hospital stay could be the reason to postpone vaccination. Moreover, vaccinations performed in hospitals with a NICU (with usually more severe ill infants) were less timely. These results are in line with results of Langkamp and Langhough38 who concluded that physicians are likely to postpone vaccination in PT infants in case of persistent morbidity.
Unlike PT and FT infants, EPT infants are likely to remain hospitalized 2 months after birth because the Dutch pediatric policy is to keep infants hospitalized until the GA would have been at least 36 weeks. When vaccination is not performed in a hospital, the child health care centre must administer the first dose after hospital discharge and is therefore automatically (too) late. Slack and Thwaites39 also found that infants who were eligible for the first immunization in the neonatal unit were vaccinated with more delays when the vaccination was not performed in the hospital.
When an infant is discharged from the hospital just before the first vaccination, a delay is possible because of practical problems in the transference of care from a hospital to a child health care centre. There may be, for example, doubt about who is responsible for administering the vaccinations. Initiatives to formulate a national guideline to improve the cooperation between hospitals and child health care centers will likely reduce this problem in the future. In 3 Dutch municipal health service regions, there are already local guidelines about the cooperation between hospitals and child health care centers.40 Two of these 3 regions indeed have high percentages of EPT infants vaccinated on time (84.3% and 78.4% versus the overall rate of 66.1%). The effect of different regional vaccination policies is also seen by the large differences in the timeliness of the first vaccination between municipal health service regions. Centralizing the management of the NIP from 2008 onwards and trying to harmonize regional policies will possibly decrease these differences in the future.
The country of birth of the parents was associated with the timeliness of the first vaccination after adjustment for the other variables. In general, infants with Dutch parents were more often vaccinated on time compared with infants with parents born in other countries (except for EPT infants with both parents born in the Netherlands Antilles and for FT infants with 1 parent born in the Netherlands and the other born in Turkey). In the Netherlands, ethnic background is associated with the vaccination uptake as well. Van Lier at al41 concluded that migrant groups are willing to vaccinate, but that they are less likely to complete the full NIP on time. Moreover, we observed that living in a very highly urbanized municipality was associated with vaccination delays. These results are in line with the results of Dombkowski et al42 who found a relationship between urban residence and vaccination delays of the DTP4 vaccination. As with ethnic background, the exact reason for this effect of urbanization rate is unclear and needs to be further evaluated.
In contrast to previous studies,42–44 we observed no clear trend between the moment of vaccination and SES. The fact that we used values for SES at the municipality level instead of individual data could have contributed to this discrepancy.
The strength of our study is that we used both GA and BW as a measure for prematurity instead of BW alone. In addition, we used a nationwide study population as registered in Præventis. Based on the number of living newborns in the Netherlands in 2006–2010 according to Statistics Netherlands,45 we calculated that 99% of the newborns were included in Præventis. Therefore, the results show an accurate picture of the timeliness of vaccination in the Netherlands. Moreover, we assessed characteristics associated with delayed vaccination in EPT, PT and FT infants separately instead of the total population.
We do also acknowledge some limitations. First, there are limitations in the registration of GA and BW in Præventis. We excluded infants with missing data for GA or BW because we could not categorize them, but the proportion of infants vaccinated on time was considerably lower for infants with missing information than for infants without missing information (32.0% vs. 81.7%, respectively). However, cases with missing data for GA or BW only accounted for a very small proportion of the total population (0.1%); therefore, it is very unlikely that it has strongly affected our results. Another problem in the registration of GA and BW is that these values are being reported by the parents during the newborn screening. Perhaps the memory of the parents is not always accurate and errors in writing down or in entering the data into the database are possible. As a result, possible misclassifications could have occurred, although the magnitude of recall bias may be limited because the newborn screening takes place within 7 days after birth. We also excluded cases with unrealistic values for GA and BW. Repeating analyses without excluding the outliers in terms of BW did not affect the results (data not shown). Therefore, we believe this limitation had a minor impact on the results.
The second limitation is that we were constricted to variables available in Præventis to assess characteristics associated with the timeliness of the first vaccination. Variables that were found to be associated with the timeliness of vaccination such as family size, birth order and marital status of the mother42,43 were not available. We also did not have individual data on SES and urbanization rate. We used the values at the municipality level as a proxy for the individual data, but individual data would be more precise and possibly would have led to different results.
For the development of interventions to improve the timeliness of vaccination, it is important to know more about the reasons behind vaccination delays among specific groups. The further improvement of the timeliness of the first DTaP-IPV vaccination might be possible if we could understand the differences in vaccination policies between regions with relatively good and poor timeliness (learn from “best practices”).
Our study showed a delay in the first immunization of preterm and low birth weight infants, but FT as well as NBW infants also received their first vaccination later than recommended in 18% of the cases. As a result, infants are at increased risk of vaccine-preventable infections, such as pertussis. Although Dutch infants receive their first vaccination on time more often compared with other countries, further improvement is possible. Our study showed that previous efforts to increase vaccination timeliness have paid off. It is important to exert continued efforts in increasing the timeliness of vaccination.
Further research is necessary to identify specific reasons for the delays. Hereby, regional differences in the timing of vaccination should get special attention because these differences indicate different vaccination policies. Future research can be used as the input for developing interventions to further improve the timeliness of vaccination.
The authors would like to thank the senior consultants on immunization and screening (RIVM) for discussing the results and possible explanations for these results and Dr. R. Knol (Erasmus Medical Center, Sophia Children’s Hospital) for his interest in the study and his expert opinion.
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